PROJECT SUMMARY Marfan syndrome is caused by fibrillin-1 mutations and results in aortic root dilation, dissection or rupture and death at around 35-45 years of age in absence of medical treatment and/or surgical intervention. Current guidelines for the prophylactic treatment of aortic root enlargement rely on two medications: ?-blocker Atenolol, a cardio-selective hypotensive agent, and the more recent angiotensin II receptor type 1(ATR1) blocker (ARB) Losartan, which reduces blood pressure with a unique anti-transforming growth factor (TGF-?) effect. However, their mode of action and effects on aortic root enlargement are controversial. A large-scale clinical trial has failed to reproduce the expected superiority of Losartan over Atenolol, which suggests that our comprehension of MFS pathogenesis and patient management approaches is incomplete, and that better and more effective options should be explored. Our research team recently reported that hypotensive MFS animals develop aortic root enlargement identically to normotensive animals, which suggests that lowering of blood pressure might not be the primary mechanism of action of MFS-associated medications, a concept that warrant further investigations. Also, we have been able to show that Losartan blocks aortic root enlargement in MFS animals lacking normal angiotensin receptor ATR1 expression, indicating an off-target effect. Our findings also indicate that Losartan inhibition of MFS aortic root enlargement is entirely mediated via increased endothelial function. This concept is further supported by our recent published animal data showing that chronic activation of endothelial function by mild aerobic exercise also attenuates MFS aortic root enlargement. Therefore, we hypothesize that optimal improvements in endothelial function using clinically relevant approaches will attenuate MFS-associated aortic root enlargement, leading to MFS aortic root stability. To test this hypothesis, three Specific Aims are proposed: Aim #1: To confirm that mild aerobic exercise or combination of exercise and Losartan can confer aortic root protection in MFS mice in an eNOS-dependent manner. Aim #2: To identify an ARB superior to Losartan in terms of increasing endothelial function, correcting aortic signaling and preventing MFS aortic root widening. Aim #3: To determine whether other clinically-relevant non-ARB medications that are known to increase endothelial function can block aortic root dilation in an eNOS-dependent fashion. To address the aims, we utilize pharmacological (available patient-ready drugs) and genetic (by generating new transgenic mouse models) approaches to manipulate endothelial function by increasing the activity of endothelial nitric oxide synthase (eNOS) in the aortic tissue in MFS mice. The ultimate goal is to explore more effective therapies that lead to better clinical outcomes in terms of aortic root remodeling and aneurysm progression in MFS or other related vascular complications.